Epidemic dengue fever and dengue hemorrhagic fever are major public health problems in the Americas. Current control measures used against the primary dengue virus (DENV) mosquito vector, Aedes aegypti, include source reduction to control juveniles and space spraying to control adults. This has not proven to be sufficient or sustainable to stem the tide of dengue. New approaches are needed to control Ae. aegypti and prevent dengue infections. Aedes aegypti feeds predominantly indoors and almost exclusively on humans. The Casa Segura (safe house) exploits long-lasting insecticide-treated materials in the form of deltamethrin-treated curtains to preclude Ae. aegypti from the home: the epidemiologically most significant point of contact between this vector and humans. The Casa Segura prevents infected vectors from entering homes and transmitting DENV to humans or uninfected vectors from becoming infected when feeding on DENV-infected humans in the home, thereby interrupting virus transmission at two points in the mosquito-human cycle. Casa Segura offers the exciting promise of sustainable prevention and perhaps even local elimination of dengue. The effectiveness of the Casa Segura to reduce dengue is predicated upon operational effectiveness of pyrethroid insecticides. Knock-down resistance (kdr) to pyrethroids has emerged in Ae. aegypti in the tropical world, but little is known about the extent to which this may adversely affect operational vector control. In this ICIDR program, we will: 1) demonstrate in a metropolitan setting (Merida, Mexico) that the Casa Segura reduces indoor abundance of DENV-infected Ae. aegypti females and dengue infections among the residents, 2) reveal the potential operational effects of kdr on the entomological and epidemiological study outcomes, and 3) determine if the Casa Segura promotes evolution of kdr in Ae. aegypti. The ICIDR consortium will include Colorado State University, Universidad Autonoma de Nuevo Leon, and Universidad Autonoma de Yucatan. Our overarching goals are to: 1) develop a broadly applicable, inexpensive and sustainable approach to make homes in the developing world as safe as those in the developed world from transmission of vector-borne pathogens, and 2) to transfer tools and technologies to our consortium and other institutions in dengue-endemic areas. RELEVANCE : The emergence of epidemic dengue fever and dengue hemorrhagic fever in the Americas is a public health catastrophe. There is no vaccine for dengue; thus more effective vector control is critical. The Casa Segura potentially provides a long term inexpensive approach to preventing dengue virus transmission in the home. The approach may also be applicable to other globally important vector borne diseases, such as malaria, filariasis, and Chagas, which are also transmitted principally in the home.